Ethanol-propylene Glycol Research Articles

DETERMINATION OF POLYPHENOLIC COMPOUNDS IN PHYTOEXTRACTS WITH ANTIBACTERIAL PROPERTIES AND STUDY POTENTIAL EFFECTS

Objectives. The research work is a comparative study of the polyphenolic compounds and flavonoid content of the phytoextracts obtained from the ultrasonic extraction process (Stegler DG-360) with 95% ethanol and ethanol-propyleneglycol mixture (in 95 : 5 ratio) from the Clove buds (Caryophyllos aromaticus L. Myrtaceae), hibiscus flowers (Hibiscus sabdariffa L. (Hs, roselle; Malvaceae)) and common yarrow (Achillea millefolium L. Asteraceae) plants, which are rich in biologically active substances with high therapeutic effect, as well as their devoted to the investigation of antioxydant activity and antimicrobial potential. Material and methods. The research work was carried out in the Central Research and Application Laboratory of Ağrı İbrahim Çeçen University (MERLAB), Republic of Turkey, using a Japanese Shimadzu brand Mistral-AB SCIEX 4000 QTRAP liquid chromatograph-mass spectrometer device. Results.It was found that in both extraction processes, the active substances penetrated sufficiently from the medicinal-plant raw materials into the extractant. 20 names of compounds containing polyphenol, flavonoid and anthocyanin derivatives have been determined. However, the amount of active substances in the phytoextract obtained with the presence of the penetrate (propylene glycol) was higher. In particular, rutin ( 75.74 ± 4.91mg/g), quercetin (110.12 ± 1.30 mg/g), gallic acid (4503.19 ± 46.83mg/g), quinic acid (4041.99 ± 187.3 mg/g), chlorogenic acid (582.30 ± 1.30mg/g), vanilin (155.6g/g1 ± 3.95mg/g) prevailed. Conclusion. The research work proves once again that the studied phytoextracts are rich in polyphenolic compounds and flavonoids. The amount of biologically active substances in the phytoextract obtained with the ethanol-propylene glycol mixture which is the penetrate substance (in the ratio of 95:5) is higher than that of the other sample (with 95% ethanol). The resulting amount of biologically active substances is a clear proof that the phytoextract has sufficient antioxidant and antimicrobial properties.

Solubility Behaviour of Aripiprazole in Different Solvent Systems

Background This current research work discusses the Aripiprazolersquos solubility behaviour in individual solvents and solvent blends to offer some theoretical foundation for the formulation scientists regarding solute solvent interactions. AimsObjectives Solubility behaviour of Aripiprazole a poorly soluble drug was studied using biocompatible solvents like polyethylene glycol 400 PEG-400 ethanol propylene glycol PG glycerin and pharmaceutically utilized solvents such as dioxane hexane and ethyl acetate in pure form and their blends. Methods Saturation solubility of Aripiprazole was studied by placing the drug in excess solvent systems using cryostatic constant temperature shaker bath for 72 hours. The solutions after equilibrium were analyzed spectrophotometrically.Results Physico-chemical characteristics of the solvents and Aripiprazole such as intermolecular interactions hydrogen bonding hydrophobic interactions and certain specific solute solvent interactions were noticed for enhanced aqueous solubility AS of Aripiprazole.Conclusion Less polar solvents were shown to significantly increase AS highlighting the hydrophobic interaction strategy. The order of cosolvents increasing AS of Aripiprazole was PEG 400 gt dioxane gt ethylacetate gt ethanol gt PG gt glycerin gt hexane. Based on the data specific combinations were shown to be helpful in the production of Aripiprazole injections and liquid orals. As a result the study produced a significant dataset for comparing how different cosolvents affected the solubility of Aripiprazole and how Aripiprazole formulations were designed.

Analgesic effect of the mint terpenoid L-carvone in sheep

ObjectiveTo determine whether L-carvone increases the voltage threshold response to a noxious electrical stimulus in sheep. Study designProspective, blinded, randomized, crossover experimental study. AnimalsA group of six healthy adult sheep. MethodsSheep were instrumented with cranial dorsothoracic subcutaneous copper electrodes. A stimulator delivered a 10 ms square-wave stimulus at 50 pps starting at 0.1 V with a 0.2 V second–1 ramp. The stimulus stopped once two observers who were blinded to treatment noted a behavioral pain response or when a 15 V cut-off was reached. Next, 0.15 mL kg–1 of either a 50% L-carvone solution or a saline-vehicle control was administered intramuscularly, and electrical threshold responses were measured every 5–15 minutes over a 6 hour period using methods identical to the baseline. One week following the first treatment (L-carvone or control), sheep were studied using identical methods with the second treatment (control or L-carvone). Drug and time effects were evaluated using a two-way repeated measures analysis of variance, and pairwise comparisons were evaluated with Holm-Sidák tests with values of p < 0.05 considered significant. ResultsL-carvone significantly increased voltage threshold responses for most time points up to 75 minutes compared with baseline and with saline control. The last time point with a significantly different response between L-carvone and saline treatments was 5 hours after drug administration. The saline-vehicle control decreased voltage threshold responses at several time points after 3 hours. Conclusions and clinical relevanceIntramuscular L-carvone is analgesic in sheep, although the ethanol-propylene glycol vehicle may cause mild hyperalgesia. This study demonstrates that a food-derived compound can be used to relieve pain in a food-producing animal.

Enhanced transdermal permeation of rasagiline mesylate nanoparticles: design, optimization, and effect of binary combinations of solvent systems across biological membrane

Rasagiline mesylate (RM) used as first-line agent for Parkinsonism exhibit low oral-bioavailability and extensive hepatic first-pass metabolism requires frequent administration. Polymeric nanoparticles of this hydrophilic drug (RM-NPs) were developed to enhance its systemic concentration and BBB crossing capacity and characterized for particle size, zeta potential; entrapment efficiency. Ex-vivo permeation study was conducted to analyze solvent-system for increased permeation of RM across biological membrane which revealed RM showed maximum flux (96.66 ± 4.63 µg/cm2/h) at 8.36 ± 0.39h with 33% propylene glycol–ethanol while RM-NPs in distilled water showed 94.16 ± 3.62 µg/cm2/h flux at 6.80 ± 0.31h indicating that 33% propylene glycol–ethanol can serve as solvent-of-choice for transdermal delivery of rasagiline.

Potency Analysis of Medical Marijuana Products from New York State.

Introduction: In the United States, medical marijuana programs have been established in 29 states and the District of Columbia. In 2014, New York State (NYS) approved medical marijuana legislation, and its program became fully operational in January of 2016. Products manufactured under the auspices of the program may be used by certified patients in NYS for the treatment of 1 of 12 qualifying medical conditions. The NYS statute requires rigorous testing of each product lot manufactured in the state for its cannabinoid profile, bacterial and fungal contamination, mycotoxins, heavy metals, plant-growth regulators, and pesticides. Here, we report on the analysis of product cannabinoid profiles.Methods: A method employing a simple extraction/dilution technique and reversed-phase high-performance liquid chromatography with photodiode array detection (HPLC-PDA) was developed for the analysis of 10 cannabinoids: cannabidiolic acid, cannabigerolic acid, cannabigerol, cannabidiol (CBD), tetrahydrocannabivarin, cannabinol, Δ9-tetrahydrocannabinol (Δ9-THC), cannabichromene, cannabidivarin, and Δ9-tetrahydrocannabinolic acid-A. The method employed internal standard quantitation and incorporated a surrogate to monitor extraction efficiency and analytical recovery.Results: The HPLC-PDA method was validated using sample matrices composed of medium-chain triglycerides, hemp oil, sesame oil, and an ethanol-propylene glycol tincture. Limits of detection, limits of quantitation, accuracy, precision, and inter- and intraday reproducibility were found to be highly satisfactory. The validated method has been used to analyze over 3500 samples from over 700 lots of medical marijuana products manufactured in NYS from January 2016 through April 2018. Quality-control data showed quantitative spike recoveries and, for the analysis of samples from the same lot, the coefficients of variation for the principal analytes, Δ9-THC and CBD, averaged <3%. Using the HPLC-PDA method, the NYS medical marijuana products were analyzed to verify the potencies on the product labels and to determine the stability of the products.Conclusions: An HPLC-PDA-based method was developed, validated, and employed to analyze 10 cannabinoids in a variety of medical marijuana products. The method has proven to be accurate, precise, stable, and very robust. Its use is an integral part of the NYS Medical Marijuana program for validation of the content and consistency of medical marijuana products.

The effects of repeated nitroglycerin administrations in rats; modeling migraine-related endpoints and chronification

BackgroundRodent models typically use a single nitroglycerin injection to induce migraine, yet migraine in clinical populations presents as recurrent episodes. Further, these models quantify behavioral endpoints that do not align with the clinical features of episodic migraine or migraine chronification and therefore may limit translational relevance. New methodRats received 5 nitroglycerin (10mg/kg/2ml), propylene glycol/ethanol vehicle, or saline injections every third day over 15days. Behavioral endpoints were assessed 110min post nitroglycerin administration and included time spent light/dark chambers for photophobia as well as activity, facial pain expressions, and tactile allodynia. ResultsAnimals administered nitroglycerin displayed photophobia, decreased activity, and increased facial pain expression. Similar alterations in photophobia and activity were seen in the vehicle treated animals, but these tended to diminish by the 4th or 5th injection. The presentation of spontaneous tactile allodynia was observed in the nitroglycerin group by the 5th episode. Comparison with existing methodsMost NTG migraine models entail a single NTG administration and quantification of evoked allodynia. This paradigm employs recurring NTG episodes and clinically-relevant measures of photophobia, hypoactivity and facial grimace endpoints as well as introduces a novel arena apparatus to quantify spontaneous allodynia. ConclusionsThis repeated NTG procedure and endpoint measures aligns with the frequency and clinical presentation of episodic migraine and its chronification, respectively. Further, propylene glycol ethanol vehicle contributes to migraine endpoints.

Dermal nanocrystals from medium soluble actives – Physical stability and stability affecting parameters

Nanocrystals are meanwhile applied to increase the dermal penetration of drugs, but were applied by now only to poorly soluble drugs (e.g. 1–10μg/ml). As a new concept nanocrystals from medium soluble actives were produced, using caffeine as model compound (solubility 16mg/ml at 20°C). Penetration should be increased by (a) further increase in solubility and (b) mainly by increased hair follicle targeting of nanocrystals compared to pure solution. Caffeine nanocrystal production in water lead to pronounced crystal growth. Therefore the stability of nanocrystals in water–ethanol (1:9) and ethanol–propylene glycol (3:7) mixtures with lower dielectric constant D was investigated, using various stabilizers. Both mixtures in combination with Carbopol® 981 (non-neutralized) yielded stable nanosuspensions over 2months at 4°C and room temperature. Storage at 40°C lead to crystal growth, attributed to too strong solubility increase, supersaturation and Ostwald ripening effects. Stability of caffeine nanocrystals at lower temperatures could not only be attributed to lower solubility, because the solubilities of caffeine in mixtures and in water are not that much different. Other effects such as quantified by reduced dielectric constant D, and specific interactions between dispersion medium and crystal surface seem to play a role. With the 2 mixtures and Carbopol® 981, a basic formulation composition for this type of nanocrystals has been established, to be used in the in vivo proof of principle of the new concept.

Nanocrystals of medium soluble actives--novel concept for improved dermal delivery and production strategy.

After use in oral pharmaceutical products, nanocrystals are meanwhile applied to improve the dermal penetration of cosmetic actives (e.g. rutin, hesperidin) and of drugs. By now, nanocrystals are only dermally applied made from poorly soluble actives. The novel concept is to formulate nanocrystals also from medium soluble actives, and to apply a dermal formulation containing additionally nanocrystals. The nanocrystals should act as fast dissolving depot, increase saturation solubility and especially accumulate in the hair follicles, to further increase skin penetration. Caffeine was used as model compound with relevance to market products, and a particular process was developed for the production of caffeine nanocrystals to overcome the supersaturation related effect of crystal growth and fiber formation - typical with medium soluble compounds. It is based on low energy milling (pearl milling) in combination with low dielectric constant dispersion media (water-ethanol or ethanol-propylene glycol mixtures) and optimal stabilizers. Most successful was Carbopol(®) 981 (e.g. 20% caffeine in ethanol-propylene glycol 3:7 with 2% Carbopol, w/w). Nanocrystals with varied sizes can now be produced in a controlled process e.g. 660 nm (optimal for hair follicle accumulation) to 250 nm (optimal for fast dissolution). The short term test proved stability over 2 months of the present formulation being sufficient to perform in vivo testing of the novel concept.

Enhanced permeation of fentanyl from supersaturated solutions in a model membrane

The aim of the present study was to investigate the permeation of fentanyl from supersaturated formulations when applied to silicone membrane. Silicone was chosen in order to separate the effects of supersaturation from other possible influences of volatile formulation components on biological membranes. Supersaturated formulations containing either propylene glycol/water (PG/H 2O) or propylene glycol/ethanol (PG/Et) were prepared containing varying degrees of saturation (DS) of fentanyl. Permeation of finite and infinite doses of the PG/H 2O formulations, and finite doses of the PG/Et formulations was investigated using Franz-type diffusion cells. For the PG/H 2O formulations a good correlation between the flux and the DS of the formulation up to 5 DS for infinite dose studies ( r 2 = 0.99), and up to 7 DS for finite dose studies ( r 2 = 0.98), was evident. Similarly, for the PG/Et formulations there is a good correlation between the mean flux and the theoretical DS of the formulation ( r 2 = 0.95). Except for the 2 DS formulations, no significant differences were seen in the mean flux between PG/H 2O and PG/Et finite dose studies. The larger fluxes observed for infinite doses of the PG/H 2O formulations versus finite doses reflect changes in the effective area of diffusion over the time of the experiment for the latter set of experiments. The permeation enhancement observed for PG/Et formulations confirms that enhanced drug thermodynamic activity was induced by ethanol evaporation.

An oil-free microemulsion for intravenous delivery of diallyl trisulfide: Formulation and evaluation

The aim of the present study was to develop an oil-free o/w microemulsion, Cremophor EL:ethanol–propylene glycol:saline, for diallyl trisulfide (DATS) for intravenous (i.v.) administration to modify the safety and pharmacokinetics of DATS. The ternary diagram was constructed to identify the regions of dilutable microemulsions, and the optimal composition of microemulsion was determined by evaluation of injection safety such as hemolysis, intravenous stimulation and injection anaphylaxis compared to commercial formulation Chentian ®. Promising microemulsion with modified injection safety was developed that could incorporate 100 mg/g of DATS. The droplet size of the microemulsion was about 26 nm in diameter with narrow distribution (polydispersity index: 0.14). Acute toxicity test showed that median lethal dose (LD 50) of DATS microemulsion was 1.69-fold higher than that of Chentian ®. Pharmacokinetics was assessed by comparing with the commercial injection after intravenous administration to rats at a dose of 30 mg/kg. The developed microemulsion showed significant higher area under the drug concentration–time curve and lower clearance and distribution volume than those of Chentian ® ( p < 0.05). This helped DATS to reach higher level in vessel, and circulate in the blood stream for a longer time resulting in better therapeutic effect. In conclusion, microemulsion would be a promising intravenous delivery system for DATS.

Quantitative evaluation of sebum lipid components with nuclear magnetic resonance

A NMR spectroscopic method is described that enables the quantitation of specific lipid classes and components, independent of fatty acid composition. We demonstrate this method for measuring cholesterol, squalene, and pools of sterol esters, wax esters (WEs), and triglyceride (TG) components in sebum and meibum. When 600 MHz NMR equipment is used in conjunction with highly sensitive cryogenically cooled probes, this method has adequate sensitivity, and for some applications, advantages over commonly used HPLC-evaporative light-scattering detection and mass spectrometry-based approaches. This method is shown to be useful for preclinical and clinical monitoring of the efficacy of sebum-reducing agents in animals and humans. In Syrian hamsters, 3% topical flutamide and 20 mg/kg oral isotretinoin reduced sterol esters by 18.7% and 30.0%, respectively, and reduced WEs by 32.9% and 31.8%, respectively, as measured in a punch biopsy of the ear. In a 72 patient clinical methodology study, the assay delivered reproducible and noninvasive measurements of WEs, cholesteryl esters, TGs, and squalene from Sebutape skin blots. The quantitative results of sebum analysis obtained by the NMR method correlate well with those obtained with HPLC-based approaches. This approach may be broadly applicable to cases in which fatty acid-independent quantification of lipid classes is desired.

Solubility Prediction of Paracetamol in Binary and Ternary Solvent Mixtures Using Jouyban-Acree Model

The Jouyban-Acree model has been used to predict the solubility of paracetamol in water-ethanol-propylene glycol binary and ternary mixtures based on model constants computed using a minimum number of solubility data of the solute in water-ethanol, water-propylene glycol and ethanol-propylene glycol binary mixtures. Three data points from each binary solvent system and solubilities in neat solvents were used to calculate the binary interaction parameters of the model. Then the solubility at other binary solvent compositions as well as in a number of ternary solvents were predicted, and the mean percentage deviation (+/-S.D.) of predicted values from experimental solubilities was 7.4(+/-6.1)%.

Evaluation of the true precocious puberty rats induced by neonatal administration of Danazol: therapeutic effects of nourishing "Yin"-Removing "Fire" Chinese herb mixture.

BackgroundNourishing "Yin"-Removing "Fire" Chinese Herb Mixture, a traditional herb-based formulation, has been successfully used for the management of idiopathic true precocious puberty (IPP) for more than thirty years. Precocious puberty rat model by neonatal administration of Danazol was used to investigate the effects of the herb mixture on the advanced sexual development of the rats, and the expression of hypothalamic gonadotropin-releasing hormone (GnRH), which is the important regulator for the hypothalamus-pituitary-gonadal axis, particularly at puberty.MethodsFemale Sprague-Dawley rats were divided into five groups: intact normal (N), IPP model (M), vehicle with no IPP (V), IPP model exposed to herb mixture (HM) and IPP model exposed to saline (S). Rats at 5 days of age were given a single subcutaneous injection of 300 microgram of Danazol dissolved in 25 microliter vehicle of propylene glycol-ethanol (1:1, v/v), to establish the precocious puberty model. From the day 15, rats in HM and S groups were continuously fed with either Nourishing "Yin"-Removing "Fire" Chinese Herb Mixture 2 ml or saline 2 ml, until 3 consecutive regular estrous cycles were established. The day of vaginal opening and the day of setup regular estrous cycle of the rats were observed. Blood concentration of estrogen was determined by radioimmunoassay. Immunohistochemistry and RT-PCR analysis were used to explore the expression of GnRH.ResultsThe day of vaginal opening and first estrous showed significant advancement in M compared with N and V (p < 0.05, respectively). The blood estrogen level increased significantly in M compared with those in other groups (about 28 days of age, at the time of vaginal opening in M rats) (p < 0.05, respectively). GnRH cells in rostral medial septum (MS), Broca diagonal band nucleus (DBB) and the medial preoptic area (MPOA), were calculated. The number in M was less than those in N and V (p < 0.05, respectively). The number was significantly higher in HM than that in M (p < 0.05). The GnRH mRNA expression increased significantly in M compared with that in N and V (p < 0.05).ConclusionThe true precocious puberty model by neonatal administration of Danazol in female rats showed augmented expression of hypothalamic GnRH; the Nourishing "Yin"-Removing "Fire" Chinese Herb Mixture down-regulated the increased GnRH expression, and significantly delayed the sexual development of the precocious puberty rat.

Prediction of benzodiazepines solubility using different cosolvency models

The solubility of four benzodiazepines (BZPs) including diazepam (DIZ), lorazepam (LRZ) clonazepam (CLZ), and chlordiazepoxide (CHZ) in water-cosolvent (ethanol propylene glycol and polyethylene glycol 200) binary systems were studied. In general, increasing the volume fraction of cosolvents resulted in an increase in the solubility of benzodiazepines. The mole fraction solubilities were fitted to the various cosolvency models, namely extended Hildebrand approach (EHA), excess free energy (EFE), combined nearly ideal binary solvent/Redlich-Kister (CNIBS/R-K), general single model (GSM), mixture response surface (MR-S), double log-log (DL-L), and linear double log-log (LDL-L). The results showed that DL-L model was the best model in predicting the solubility of all drugs in all the water–cosolvent mixtures (OAE%=4.71). The minimum and maximum errors were observed for benzodiazepine's solubility in water–propylene glycol and water–ethanol mixtures which were 2.67 and 11.78%, respectively. Three models (EFE, CNIBS/R-K and LDL-L) were chosen as general models for solubility descriptions of these structurally similar drugs in each of the solvent systems. Among these models, the EFE model was the best in predicting the solubility of benzodiazepines in binary solvent mixtures (OAE%=11.19).

Cardiovascular activity of a methanolic extract of Digitalis purpurea spp. heywoodii

The paper deals with the effects of a glycosidal extract of Digitalis heywoodii, ssp. of Digitalis purpurea L., (Schrophulariaceae) grown in Badajoz (Spain), on isolated cardiac auricle of rabbits, urinary excretion of rats, as well as its emetic effect in pigeons. These effects using vehicle (propylene glycol–ethanol–water, 40:10:50) and digoxin as standards are presented. The extract at concentrations of 20 and 40 μg/ml produced an increase in the contraction force of auricles in a dose-dependent way. At doses of 15 and 30 mg/kg a slight diuretic and natriuretic effect was observed. The active dose range for emesis was 0.5–4 mg/kg and a decrease of the emesis time within 10 min of injection in dose-dependent manner was obtained. The pharmacological activity of the extract is related to gitoxin derivatives (digitalinum verum and strospeside), the most abundant compounds obtained from the leaves of Digitalis purpurea spp. heywoodii.

Transdermal delivery of tacrine: I. Identification of a suitable delivery vehicle

Peroral administration of tacrine, a drug approved for the treatment of Alzheimer's disease, is associated with low bioavailability (due to first-pass effect), short elimination half-life and reversible hepatotoxicity. Transdermal administration may reduce the degree of these problems. In this investigation the influence of three commonly used solvents (water, propylene glycol and ethanol), and their mixtures, on the in vitro permeation of tacrine through rat and human skin were evaluated. Maximum flux and permeability were observed from ethanol-propylene glycol and water-ethanol binary mixtures, respectively. The permeability of tacrine through rat skin was about 2.5 times higher than that through human skin. Excellent correlation between the rat and human skin data was observed. The flux from the ethanol-propylene glycol binary mixture was 98 μg/cm 2 per h through rat skin and was selected for in vivo transdermal administration. The observed in vivo tacrine plasma concentrations were in good agreement with the concentration-time profile simulated using in vitro flux and tacrine clearance in rat. Preliminary short-term (24 h) irritation studies did not indicate any irritation. The results from this investigation indicate that transdermal delivery of tacrine may be feasible and that the ethanol-propylene glycol (1:1) mixture appears to be a promising solvent system.

Role of the appendageal pathway in the percutaneous absorption of pyridostigmine bromide in various vehicles.

We studied the percutaneous absorption of [14C]-labelled pyridostigmine bromide mixed into various vehicles through normal and appendage-free scar rat skin, in vitro during 72 h. At the end of the experiment, the percentages of the drug absorbed were higher for nerol 8% in ethanol (respectively 78.4 +/- 3.6% and 72.8 +/- 4.5% on normal and scar skin) and azone 5% in ethanol-propylene glycol (90:10) (respectively 76.4 +/- 4.4% and 57.2 +/- 7.1% on normal and scar skin). Propylene glycol 10% in ethanol inhibits pyridostigmine absorption: 9.9 +/- 2.6% and 2.2 +/- 1.2% vs 14.7 +/- 3.8% and 5.5 +/- 5.1% with ethanol on control and scar skin. The transappendageal pathway seems to be less important for nerol (55% to 82% of the absorption routes between 4 h and 32 h) and azone (60% to 79% of the absorption routes until 32 h) than for propylene glycol (63% to 96% of the absorption pathways during the whole experiment), dimethylsulfoxide (about 78% during the first 32 h) and ethanol (more than 50% during most of the time). These results show that it is possible to increase or decrease the percutaneous absorption, as well as to modulate the relative importance of the transepidermal route and the transfollicular pathway.

Evaluation of a new penetration enhancer 1-[2-(decylthio)ethyl]azacyclopentan-2-one (HPE-101).

A new compound, 1-[2-(decylthio)ethyl]azacyclopentan-2-one (HPE-101) was synthesized, and its skin penetration enhancing activity was examined by using 14C-indomethacin as a penetrant. A solution of HPE-101 and indomethacin was applied to a cloth pad affixed onto an adhesive tape to give a HPE-101 patch, and the patch was applied to hairless mouse skin. The amount of percutaneously absorbed indomethacin was determined by measuring the radioactivity excreted in urine for 24 h after application. 1) Azone and decylmethyl sulfoxide, enhanced markedly the percutaneous absorption of indomethacin when the propylene glycol-ethanol (9:1 v/v) mixture was used as the solvent. 2) Among various penetration enhancers dissolved in the indomethacin solutions and applied to screen for penetration enhancing activity, HPE-101 was found to be the most prominent. 3) Solvents containing more than 3% (w/w) of HPE-101 produced a plateau level of the penetration enhancing activity. 4) Daily application of 1% (w/w) solutions of HPE-101 or Azone increased the daily excretion of indomethacin significantly above the level excreted on the previous day. However, repeated daily application beyond 3 d gave a steady state excretion of indomethacin. 5) The mouse skin was pretreated with 3% (w/w) solutions of HPE-101 or Azone for 24 h on the 1st day, and the indomethacin solution was applied for 24 h on the 3rd day and 7th day to examine the recovery of skin barrier function. Enhanced excretion of indomethacin was still noted on the 3rd day, but enhancement was not observed on the 7th day.

Topical All-Trans Retinoic Acid Stimulates Collagen Synthesis In Vivo

Histochemical and ultrastructural studies demonstrate that topical all-trans retinoic acid (RA) stimulates the deposition of a subepidermal band of collagen in photoaged hairless mice. The aim of this study was to examine the effect of RA treatment on collagen synthesis using biochemical and immunochemical techniques. Albino hairless mice were irradiated three times a week for 10 weeks with four minimal erythema doses of UVB from Westinghouse FS-40 bulbs. In the post-UV period, mice were either nontreated or treated with 0.05% RA or the ethanol-propylene glycol vehicle for up to 10 weeks. Antibodies against the aminopropeptide (AP) of type III procollagen were used in immunofluorescence microscopy and radioimmunoassay techniques. The AP of type III collagen is normally present throughout the dermis and in areas of active collagen synthesis (i.e., the dermal-epidermal junction). In this study, a similar distribution was seen in all untreated and vehicle-treated mice, and in mice treated with RA for 2, 4, and 6 weeks. However, increased staining, in a subepidermal band, was detected in the 8-week RA-treated skin. This region became intensely fluorescent to a depth of 100 mu in the 10-week RA-treated skins. As determined by radioimmunoassay, the content of the AP of type III procollagen increased twofold with 10-week RA treatment. Because the ratio of type I to type III collagens remained constant in treated and untreated skins, it is reasonable to assume that the content of type I collagen increased in proportion to type III collagen in RA-treated skins.

Accumulation in the lung of [ 75Se]norcholestenol administered intravenously in a globular partially quaternized poly[thio-1-(N,N-diethyl-aminomethyl)ethylene] carrier system

A novel globular partially quaternized polymer (about 80 Å in diameter) has been used as a carrier system for the intravenous administration of a labelled steroid [ 75Se]norcholestenol to rabbits. Steroid administered in the free form (ethanol-propylene glycol solution) or contained m an oil-in-water emulsion was used as a control. The distribution of the steroid was followed using gamma-scintigraphy. When entrapped within the globular polymer system, the labelled steroid was taken up to a large extent (50%) in the lungs. This effect was associated with toxic manifestations (the rabbits experienced dypnoea and dystaxia) which were due to an action of the polymer on the microvasculature. Histology showed the pulmonary veins to be engorged with blood; a blockage of the vascular system had taken place. In contrast, when the steroid was administered using a solution and an emulsion formulation, the greater quantity of the observed activity was found in the liver/spleen area (45%) whereas less activity appeared in the lung/heart region (12%).